Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience.

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en España (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective.

A rare presentation of hypovolemic shock secondary to Whipple's disease.

Whipple's disease is a rare, multisystem infection caused by the Gram-positive Tropheryma whippelii organism. In addition to neurological and rheumatological manifestations, this disease can result in significant gastrointestinal symptoms such as malabsorption, diarrhea, and weight loss. Given the diagnostic challenge and rare occurrence, a high index of suspicion is critical to prevent morbidity and mortality from this otherwise highly infectious disease transmitted via the fecal-oral route. We present a very rare but near-fatal case of hypovolemic shock secondary to protein-losing enteropathy and gastrointestinal bleeding from small bowel T. whippelii infection. Furthermore, the epidemiology, clinical presentation, diagnosis, and management of Whipple's disease is reviewed.

Tropheryma whipplei Infection (Whipple Disease) in the USA.

BACKGROUND: Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. AIMS: To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. METHODS: Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. RESULTS: Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). CONCLUSIONS: TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Whipple's disease: case report and review of the literature.

Whipple's disease (WD) is known as an infrequent, systemic, chronic infection caused by the actinomycete Tropherima whipplei (T. whipplei). The disease is frequently characterized by a long prodromal and protean extra-intestinal phase, which often causes misdiagnosis and inappropriate treatments. Herein, we describe the case a 62-year-old man with a histological diagnosis of WD established when oral steroid treatment was started due to rheumatic manifestations, triggering intestinal symptoms. Systematic review of the literature was performed to include studies where WD was eventually diagnosed on duodenal biopsies. Three patients' subgroups were identified according to the clinical presentation.

What is the best therapy for Whipple's disease? Our point of view.

Although Whipple's disease (WD) has been treated with antibiotics since the early 50s, the best antibiotics and the duration of the therapy have not yet been established. We consider here the pro and cons of the two most commonly used therapies, ceftriaxone followed by trimethoprim-sulfamethoxazole (TMP-SMZ) and hydroxychloroquine in combination with doxycycline. The therapy based on ceftriaxone and TMP-SMZ is efficient in the vast majority of patients for the first few years. However, since reinfections or reactivations can occur, a life-long prophylaxis is necessary and doxycycline is nowadays the best option. We thus propose a therapy based on merging these to therapies together, ceftriaxone, and TMP-SMZ for the first year(s) and then life-long prophylaxis with doxycycline.

Short article: Relapsing Whipple's disease: a case report and literature review.

Whipple's disease is a rare infection caused by Tropheryma whipplei, a Gram-negative Bacillus usually found in macrophages of the lamina propria of the small intestine. The typical clinical manifestations of classic Whipple's disease are diarrhea, weight loss, malabsorption, abdominal pain, and arthralgia. The disease's laboratory diagnosis is currently based on duodenal biopsy. Treatment generally includes primary therapy for 2 weeks with intravenous antibiotics capable of reaching high levels in the cerebrospinal fluid, such as ceftriaxone, usually followed by treatment with oral cotrimoxazole for 1 year. Early diagnosis should enable appropriate treatment and improves the prognosis, and prolonged antibiotic treatment often leads to complete remission. Our case report focuses on a 72-year-old man who had been passing watery stools for 1-2 months, accompanied by low-grade fever. He reported profound asthenia, a weight loss of about 3 kg, and loss of appetite. Thirty years earlier (in 1984), he had been working as a horse keeper at a University Department of Agricultural and Veterinary Studies, where he had contracted Whipple's disease. Laboratory tests and microbiological studies led to a diagnosis of recurrent Whipple's disease. Esophagogastroduodenoscopy was performed under deep sedation. Biopsy samples obtained from the stomach and duodenum were stained with hematoxylin and eosin, Giemsa, and periodic acid-Schiff to identify any accumulation of typical periodic acid-Schiff-positive macrophages in the lamina propria. A specific quantitative real-time PCR assay using specific oligonucleotide probes for targeting repeated sequences of Tropheryma whipplei was also performed to detect its DNA in the duodenum samples.

Treatment of classic Whipple's disease: from in vitro results to clinical outcome.

OBJECTIVES: Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine. METHODS: Our laboratory has been a reference centre since the first culturing of Tropheryma whipplei, and we have tested 27,000 samples by PCR and diagnosed 250 cases of classic Whipple's disease. We report here the clinical course of patients who were followed by one of our group. RESULTS: Of 29 patients, 22 (76%) were previously treated with immunosuppressive drugs, 26 (90%) suffered from arthralgias and 22 (76%) exhibited weight loss. Intravenous initial treatment was paradoxically associated with an increased risk of failure (P = 0.0282). Treatment with doxycycline and hydroxychloroquine (± sulfadiazine or trimethoprim/sulfamethoxazole) was associated with a better outcome (0/13 failures), whereas all 14 patients who were first treated with trimethoprim/sulfamethoxazole and referred to us (P < 0.0001) experienced failure. Among the patients treated with doxycycline and hydroxychloroquine after previous antibiotic treatments, two presented with a reinfection caused by different T. whipplei strains. Finally, serum therapeutic drug monitoring allowed us to detect a lack of compliance in the only patient with failure among the 22 patients treated with lifetime doxycycline. CONCLUSIONS: In vitro results were confirmed by clinical outcomes and trimethoprim/sulfamethoxazole was associated with failures. The recommended management is a combination of doxycycline and hydroxychloroquine for 1 year, followed by doxycycline for the patient's lifetime along with stringent therapeutic drug monitoring.

Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up.

Whipple disease (WD) is a rare multisystemic infection with a protean clinical presentation. The central nervous system (CNS) is involved in 3 situations: CNS involvement in classic WD, CNS relapse in previously treated WD, and isolated CNS infection. We retrospectively analyzed clinical features, diagnostic workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data in 18 patients with WD and CNS infection. Ten men and 8 women were included with a median age at diagnosis of 47 years (range, 30-56 yr). The median follow-up duration was 6 years (range, 1-19 yr). As categorized in the 3 subgroups, 11 patients had classic WD with CNS involvement, 4 had an isolated CNS infection, and 3 had a neurologic relapse of previously treated WD. CNS involvement occurred during prolonged trimethoprim-sulfamethoxazole (TMP-SMX) treatment in 1 patient with classic WD. The neurologic symptoms were various and always intermingled, as follows: confusion or coma (17%) related to meningo-encephalitis or status epilepticus; delirium (17%); cognitive impairment (61%) including memory loss and attention defects or typical frontal lobe syndrome; hypersomnia (17%); abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron (44%) or extrapyramidal symptoms (33%); and ophthalmoplegia (17%) in conjunction or not with progressive supranuclear palsy. No specific pattern was correlated with any subgroup. Brain magnetic resonance imaging (MRI) revealed a unique focal lesion (35%), mostly as a tumorlike brain lesion, or multifocal lesions (23%) involving the medial temporal lobe, midbrain, hypothalamus, and thalamus. Periventricular diffuse leukopathy (6%), diffuse cortical atrophy (18%), and pachymeningitis (12%) were observed. The spinal cord was involved in 2 cases. MRI showed ischemic sequelae at diagnosis or during follow-up in 4 patients. Brain MRI was normal despite neurologic symptoms in 3 cases. CSF cytology was normal in 62% of patients, whereas Tropheryma whipplei polymerase chain reaction (PCR) analysis was positive in 92% of cases with tested CSF. Periodic acid-Schiff (PAS)-positive cells were identified in cerebral biopsies of 4 patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years (range, 1-7 yr) with either oral monotherapy (TMP-SMX, doxycycline, third-generation cephalosporins) or a combination of antibiotics that sometimes followed parenteral treatment with beta-lactams and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow-up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Thirteen patients (72%) had stopped treatment for an average time of 4 years (range, 0.7-14 yr). Four patients had clinical worsening despite antimicrobial therapy; 2 of those died following diffuse encephalitis (n = 1) and lung infection (n = 1). In conclusion, the neurologic manifestations of WD are diverse and may mimic almost any neurologic condition. Brain involvement may occur during or after TMP-SMX treatment. CSF T. whipplei PCR analysis is a major tool for diagnosis and may be positive in the absence of meningitis. Immune reconstitution syndrome may occur in the early months of treatment. Late prognosis may be better than previously reported, as a consequence of earlier diagnosis and a better use of antimicrobial therapy, including hydroxychloroquine and doxycycline combination.

Whipple's disease infection surgical treatment: presentation of a rare case and literature review.

The Whipple' Disease (W.D.) is a very rare disease with an incidence of 1 per 1.000.000 inhabitants; it is a systemic infection that may mimic a wide spectrum of clinical disorders, which may have a fatal outcome and affects mainly male 40-50 years old. The infective agent is an actinomycete, Tropheryma Whipplei (T.W.) that was isolated 100 years after first description by Wipple, and identified in macrophages of mucosa of the small intestine by biopsy which is characterized by periodic acid-Schiff-positive, products of the inner membrane of his polysaccharide bacterial cell wall. The multisystemic clinical manifestations evolve rapidly towards an organic decay characterized by weight loss, malabsorption, diarrhea, polyathralgia, opthalmoplegia, neuro-psychiatric disorders and sometimes associated to endocarditis. Early antibiotic treatment with trimethoprim and sulfometathaxazole reduces the fatal evolution of the disease. The authors present a rare experience about a female subject in which the clinical gastrointestinal signs were preceded by neuro-psychiatric disorders, and evolved into obstruction and intestinal perforation which required an emergency surgery with temporary ileostomy, recanalized only after adequate medical treatment with a full dose of antibiotic and resolution of clinical disease for the high risks of fistulae for the edema and lymphadenopathy of mucosa. The diagnosis was histologically examined by intestinal biopsy performed during surgery, which showed PAS-positive histiocytes, while PRC polymerase RNA was negative, which confirms the high sensibility of PAS positive and low specificity of RNA polymerase for T.W.

Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease.

During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD.

Intravenous ceftriaxone, followed by 12 or three months of oral treatment with trimethoprim-sulfamethoxazole in Whipple's disease.

BACKGROUND: There is no agreement on how and for how long Whipple's disease should be treated. In a randomized trial it was shown that patients can be cured with ceftriaxone or meropenem followed by trimethoprim-sulfamethoxazole for 12 months. The present study tested whether trimethoprim-sulfamethoxazole for three months is sufficient. METHODS: In the time from July 2004 to July 2008, 40 untreated patients from central Europe were sequentially admitted to an open-label, non-randomized extension of the previous trial with essentially an identical protocol. The modified treatment consisted of 2 g ceftriaxone intravenously once daily for 14 days followed by oral trimethoprim-sulfamethoxazole 160/800 mg twice daily for 3 months. Primary endpoint was treatment efficacy compared with the previous study. RESULTS: Twelve months of treatment with trimethoprim-sulfamethoxazole was not more effective than 3 months as indicated by clinical findings, laboratory (p = 0.405, p = 0.631, resp.), and histological data (p = 0.456). 36 of 37 surviving patients including 14 with cerebrospinal infection were in remission without evidence of recurrence after a median follow-up time of 80 months. In one patient, Tropheryma whipplei arthritis recurred 63 months after initial therapy. Secondary endpoints indicate that histology of intestinal biopsies was a more useful indicator to determine eradication of T. whipplei than PCR. In submucosal and extra-intestinal tissue, the diagnostic value of the PCR was superior. Prospective data disclosed a heterogeneous spectrum of clinical presentation and course of Whipple's disease. CONCLUSION: This study indicates that ceftriaxone followed by three months of trimethoprim-sulfamethoxazole is highly efficacious in the treatment of Whipple's disease.

In vitro activity of pentamidine against Tropheryma whipplei.

Pentamidine is a group I intron splice inhibitor used as a chemotherapeutic agent to treat parasitic infections. It was recently found to be efficient intracellularly against Coxiella burnetii, the bacterial agent of Q fever. This in vitro activity was linked to the presence of self-splicing group I introns that disrupt the 23S rRNA of C. burnetii. However, there are several indications that pentamidine may have a wider range of antibacterial activity. The aim of this study was to determine the in vitro activity of pentamidine against Tropheryma whipplei, the agent of Whipple's disease, a chronic disease for which antibiotic treatment remains challenging. In vitro susceptibility testing of pentamidine and doxycycline was assessed both in axenic medium and in cell culture against three clinical isolates of T. whipplei using a quantitative real-time polymerase chain reaction (PCR) assay as previously described. Both doxycycline and pentamidine were found to be active against T. whipplei strains both in axenic medium and in cell culture, with minimum inhibitory concentration ranges of 0.5-1mg/L and 0.125-0.25mg/L for doxycycline and pentamidine, respectively. Pentamidine was effective in vitro against T. whipplei both intracellularly and in axenic medium. This is the first evidence of the direct efficacy of pentamidine against T. whipplei grown in axenic medium and in cells. Since pentamidine has been widely used in humans, we believe that it could be an alternative drug for the treatment of this chronic disease that should be further studied in clinical trials.

Tropheryma whipplei aortic valve endocarditis without systemic Whipple's disease.

Culture-negative endocarditis is most often the result of prior antimicrobial therapy. Tropheryma whipplei is the etiologic agent of Whipple's disease, which is typically characterized by diarrhea, weight loss, and intra-abdominal lymphadenopathy. We present the case of a 48-year-old male with Whipple's endocarditis of the aortic valve who did not develop signs of systemic Whipple's disease. Our patient was treated with a regimen that included ceftriaxone for 6 weeks prior to his cardiac surgery, yet valve pathology demonstrated abundant T. whipplei, suggesting that a prolonged antibiotic course is necessary for the treatment of Whipple's endocarditis.

Failure and relapse after treatment with trimethoprim/sulfamethoxazole in classic Whipple's disease.

OBJECTIVES: Classic Whipple's disease is a chronic disease caused by Tropheryma whipplei. A recent study reported that intravenous treatment with ceftriaxone or meropenem followed by a 1 year treatment with trimethoprim/sulfamethoxazole cured all patients. However, we have previously reported that T. whipplei is poorly susceptible to beta-lactams and resistant to trimethoprim. Herein, we want to evaluate these antibiotic regimens. PATIENTS AND METHODS: Since the organism was first cultured in Unité des Rickettsies, Marseille (France), we received samples for the diagnosis of T. whipplei infections. Among the 37 patients referred to us for management, 24 patients presented classic Whipple's disease. Among them, 14 patients treated with trimethoprim/sulfamethoxazole were followed up for >3 years. RESULTS: None of the 14 patients was cured. One patient presented with an adverse side effect necessitating treatment cessation. Two patients developed an immune reconstitution inflammatory syndrome. One patient died 4 weeks after initiation of the treatment. Five patients developed clinical resistance; four of these having mutations on the target gene of sulfamethoxazole (folP). Five patients developed a relapse after cessation of trimethoprim/sulfamethoxazole after an average of 30 months. The high relapse rate may be linked to our recruitment. However, discrepancies with other centres could be due to the heterogeneity of diagnosis and cure criteria, different follow-up methods or infections due to T. whipplei strains with better susceptibility to antibiotics. CONCLUSIONS: We confirmed, as predicted from prior testing of T. whipplei susceptibility, that trimethoprim/sulfamethoxazole is not optimal for classic Whipple's disease. In addition, 1 year treatment may be followed by relapses.